Abstract
Identification of biomarkers for endometriosis is an unmet medical need that demands to be fulfilled. In this study, we first used a mouse model of endometriosis and evaluated the potential utility of select biomarkers based on serial observations. Since fibrosis is the end result of lesional development, we chose high mobility group box 1 (HMGB1), osteopontin (OPN), and hyaluronic acid (HA), all three of them have been well documented to be involved in endometriosis and fibrosis, as potential biomarkers. In addition, we performed immunohistochemistry analysis of HMGB1, OPN, and the receptors for HMGB1, such as toll-like receptor 4 (TLR4), nuclear factor κB (NF-κB), proliferating cell nuclear antigen (PCNA), interleukin-33 (IL-33), and receptor for advanced glycation endproducts (RAGE)–a pattern recognition receptor, with HMGB1 being its important ligand. We then evaluated the same set of putative markers in 30 women with ovarian endometriomas and 20 without endometriosis, and reevaluated the 3 plasma markers 3 months after the surgical removal of all visible endometriotic lesions. In mouse, the lesional staining levels of OPN, RAGE, and IL-33 were all significantly higher than that of normal endometrium, and increased progressively as lesions progressed. In contrast to HMGB1, TLR4, p-p65 and PCNA staining levels were decreased progressively. In humans, lesional staining levels of OPN correlated positively, while that of HMGB1 correlated negatively with the extent of fibrosis. All three plasma markers correlated positively with the extent of lesional fibrosis. Through this integrated approach, we identified plasma HMGB1, OPN and HA as promising admissible biomarkers for endometriosis.
Highlights
Over the last 30 years, numerous attempts have been made to identify peripheral biomarkers of endometriosis
Using a Cox regression model incorporating co-variables such as age, parity, rASRM scores, total cyst volumes, and the immunostaining levels of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), p-p65, proliferating cell nuclear antigen (PCNA), IL-33 and OPN, we found that the severity of dysmenorrhea in women with endometriosis was significantly associated with the extent of lesional fibrosis (p = 0.019) and lesional HMGB1 staining levels (p = 0.026)
In this study, using a radically different study design—theory-based, targeted discovery from animal experimentation based on the knowledge of the natural history of endometriotic lesions and validation from human samples, we found that plasma HMGB1, OPN, and hyaluronic acid (HA) are promising admissible biomarkers for diagnosing endometriosis
Summary
Over the last 30 years, numerous attempts have been made to identify peripheral biomarkers of endometriosis. Evidence accumulated in the last few years indicates that endometriotic lesions are wounds undergoing repeated tissue injury and repair (ReTIAR) and, as such, undergo progressive changes, leading to fibrosis[14,15,16,17] This dynamic and progressive nature of the disease course challenges the view that endometriosis as just one single, monolithic entity, nothing short of immutable, that may account for a seemingly disconnect between the changes in peripheral biomarkers and lesional progression and adds to the difficulty in identifying a biomarker that is specific to endometriosis. We evaluated the same set of putative markers in human endometriosis, and reevaluated 3 months after the surgical removal of all visible endometriotic lesions Through this integrated approach, we identified plasma HMGB1, OPN and HA as promising and admissible biomarkers for endometriosis
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